Polymorphism of CYP2C9 Gene for Optimization of Warfarin Therapy in Patients with Prosthetic Heart Valves

I.V. Malyarchuk, N.G. Gorovenko, О.А. Krykunov, A.R. Babochkina

Abstract


Warfarin is the oral anticoagulant most frequently used to control and prevent thromboembolic disorders. Warfarin, a coumarin derivative, inhibits vitamin K recycling by blocking its metabolism at the vitamin K-epoxide intermediate thereby decreasing the amount of available vitamin K. Warfarin has a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Warfarin is dosed using non-genetic factors, including gender, weight, and age, and is monitored by coagulation testing in order to maintain the international normalized ratio (INR). Warfarin metabolism is highly variable and depends on genetic factors. The cytochrome P450 2C9 gene CYP2C9 encodes an enzyme that metabolizes the more active isomer of warfarin (S-warfarin) to inactive products. Several variants of CYP2C9 alleles are associated with reduced enzyme activity and lower clearance rates of warfarin. Patients who carry at least one copy of such a variant allele (such as CYP2C9*2 and CYP2C9*3) have reduced metabolism and thus higher drug concentration, and require a lower daily warfarin dose than patients who are homozygous for the «wild» type CYP2C9*1 allele.
The aim of this study was to investigate the impact of CYP2C9 polymorphism on the INR values changes and warfarine dose in patients with heart valve replacement.
Materials and Methods. The study included 155 patients with heart valve replacement (67.74 % males, 32.26 % females, average age 51.7 ± 1.1 years). Patients received warfarin from initial dose of 5 mg/day, target INR values from 2.5–3.5. Subgroup A (n = 35) — patients with INR values out of therapeutic range and subgroup B (n = 120) patients with INR values from 2.5 to 3.5. For determination of allelic variant *2 *3 of CYP2C9 gene the method of allele-specific PCR has been used. Genotype frequencies were determined and Hardy-Weinberg equilibrium was tested. Differences in the warfarin dose requirement between patients with genotypes CYP2C9*1*1, CYP2C9*1*2, CYP2C9*1*3, CYP2C9*2*2, CYP2C9*3*3 and CYP2C9*2*3 were assessed with the Student’s t-test. P-value < 0.05 was considered significant.
Results. Frequencies of the genotype CYP2C9*1*1 (a «wild» type) was 66.45 %. The frequencies of the heterozygous genotypes CYP2C9*1*2, CYP2C9*1*3, homozygous genotypes CYP2C9*2*2, CYP2C9*3*3 and compound heterozygous genotype CYP2C9*2*3 were 18.06; 11.61; 0.65; 0.65 and 2.58 %, respectively.
The mean warfarin daily dose requirement was highest in patients with genotype CYP2C9*1*1 (3.70 ± 0.15 mg), compared to patients with genotypes CYP2C9*1*3 (2.47 ± 0.26 mg) and CYP2C9*2*3 (0.78 ± 0.16 mg) (P < 0.05), similar to patients with genotype CYP2C9*1*2 (3.24 ± 0.22 mg) (P > 0.05). Patients with genotype CYP2C9*1*3 had higher risk of over-anticoagulation during warfarin therapy, compared to patients with wild-type genotype (P < 0.05).
Conclusions. Genetic information on CYP2C9 gene is important both for the initial dose-finding phase and during maintenance treatment with warfarin. Testing for CYP2C9 gene variants could potentially alter clinical management in patients receiving warfarin therapy.


Keywords


warfarin; dose; gene; polymorphism; INR

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DOI: https://doi.org/10.22141/1997-2938.1.24.2014.82823

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